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Psychophysiological evidence for altered information processing in delusional misidentification syndromes
Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 365 – 372 www.elsevier.com/locate/pnpbp
Psychophysiological evidence for altered information processing in delusional misidentification syndromes Charalabos Papageorgioua,*, Errikos Ventourasb, Lefteris Lykourasa, Nikolaos Uzunogluc, George N. Christodouloua a
Psychophysiology Laboratory, Department of Psychiatry, Eginition Hospital, Medical School, University of Athens, 74 Vas. Sophias Avenue, Athens GR-11528, Greece b Department of Medical Instrumentation Technology, Technological Educational Institution of Athens, Egaleo, Athens, Greece c Department of Electrical and Computer Engineering, National Technical University of Athens, Zografou, Athens, Greece Accepted 18 November 2002
Abstract Recent research provides evidence that delusional misidentification syndromes (DMS) are associated with cognitive deficits. However, the underlying mechanisms of these deficits are not known. Since the P300 component of event-related potentials (ERPs) is related to fundamental aspects of working memory (WM), the present study is focused on P300 elicited during a WM test in DMS patients, as compared to those of healthy controls. Nine patients with DMS and 11 healthy controls, matched for age, sex and educational level were tested with a computerized version of the digit span test of the Wechsler batteries. Auditory ERPs were measured during the anticipatory period of the test. DMS patients showed significant reductions in P300 amplitude at the right frontal region compared to healthy controls. P300 latency in the central midline brain region was significantly prolonged in the DMS group. Each of these measures classified correctly 90% of the two groups. Moreover, the memory performance of the patient group was significantly lower, relatively to healthy controls. These findings provide evidence supporting the suggestion that DMS is associated with psychophysiological alterations occurring at the right frontal region, which mediates automatic processes, as well as with an irregular allocation of attentional resources, involving the interhemispheric circuitry, possibly due to gray matter degeneration. Finally, present work points to a need for further research investigating the characteristics, causes, course and treatment of severe cognitive deficits associated with DMS. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Capgras syndrome; Delusional misidentification syndromes; Event-related potentials; Fre´goli syndrome; P300; Working memory
1. Introduction The term delusional misidentification syndromes (DMS) includes the Capgras syndrome, the Fre´goli syndrome, intermetamorphosis and the syndrome of subjective doubles (Christodoulou, 1977, 1991). However, other types have been described, and it should be noted that individual cases may show features of more than one type (Christodoulou, 1978; Silva et al., 1997a). Interest in DMS has increased recently. Until the past decade, DMS was regarded as very
Abbreviations: CT, computerized tomography; DMS, delusional misidentification syndromes; EEG, electroencephalogram; EOG, electrooculogram; ERPs, event-related potentials; fMRI, functional magnetic resonance imaging; WM, working memory. * Corresponding author. Tel.: +30-107289117; fax: +30-107232042. E-mail address: [email protected] (C. Papageorgiou).
rare, but an increasing number of cases are now being reported (Joseph, 1994; Kirov et al., 1994; Huang et al., 1999). It has been suggested that DMS derive from ‘a failure to appreciate the actual identity or uniqueness of something—overriding the issue of whether it is a person, place, event or object’ (Cutting, 1991). A range of suggestions has been put forward, in order to explain the etiopathogenesis of DMS. Psychological and especially psychodynamic viewpoints attributed a decisive pathogenetic role to the defense mechanisms of splitting and projection, resulting from ambivalent feelings, induced by overintense affect towards significant others (Christodoulou, 1986; Zanker, 2000; Munro, 2000). It should be emphasized that, recently, the significance of these suggestions has been weakened, owing to the fact that a high proportion of DMS cases exhibit significant brain pathology, although the exact underlying mechanisms of this brain pathology is not clear.
0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(02)00353-6
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However, it has been suggested that the disturbance in DMS is associated with defects in right hemispheric function and/ or interhemispheric transmission (Joseph, 1986; Fleminger and Burns, 1993; Hirono and Cummings, 1999; Luaute and Bidault, 1994; Mentis et al., 1995; Phillips and David, 1995; Edelstyn and Oyebode, 1999; Dejode et al., 2001). It is widely recognized that the elucidation of the fundamental nature of pathogenetic mechanisms of psychiatric entities may lead to new tools for treatment and prevention, individualization of care, harm reduction and cures. In this perspective event-related potentials (ERPs) constitute a useful tool, providing valuable information with regard to the brain-behavior relations (Boutros et al., 1997; Fabiani et al., 2000). One particular ERP component, the auditory P300 component, generated in response to a target detection task, that occurs about 300 ms after a warning stimuli, has received a great deal of interest. This ERP component is conceptualized as the physiological correlate of updating a cognitive hypothesis, or the working memory (WM) update of what is expected in the environment and/or attentional operations involved in this function (Donchin, 1981; Donchin and Coles, 1988; Polich, 1998; Coull, 1998). Until now, there has been a lack of empirical data concerning the ERP measures on DMS. Very recently (Papageorgiou et al., 2002), we observed a patient with concomitant Capgras and Fre´goli symptoms, who showed significant and diffuse prolongation of P300 latencies compared with healthy controls, as well as significantly attenuated amplitude of P300 in right prefrontal and parietal areas. Because the P300 component was elicited during a WM test, these findings may support the notion that DMS is associated with impairments of WM. In view of the above considerations, we hypothesize that the electrophysiological brain activity, as reflected by P300, in association with WM operations, could be of value in identifying possible pathophysiological mechanisms involved in DMS. Thus, the present study is focused on P300 elicited during a WM test in DMS patients, as compared to those of healthy controls, matched for age, sex and educational level. Furthermore, the decision was taken to investigate various DMS as a whole. It is interesting to note that DMS share a number of more or less common features, i.e., it is considered that these syndromes share a common neuroanatomical basis (see above). Additionally, it has been argued that these syndromes can arise as a dysfunction at one of several levels of familiarity processing during the information process (Phillips and David, 1995). Furthermore, on a clinical level of analysis, DMS demonstrate common features, i.e., they are selective and specific in that only one or a few ‘objects’ are misidentified. The fictitious ‘other’ is a personification or other symbolic representation of the patient’s own experience, and very often demonstrates aggression (Silva et al., 1995, 1997b). Finally, the dopamine overactivity (McAllister, 1992; Roane et al., 1998) is considered as an essential substrate of all DMS, while treatment involves antipsychotic medication in
all of them (Zanker, 2000). Consequently, the abovementioned points indicate that the various DMS might be linked by a potent association, thereby justifying their investigation as a whole.
2. Methods 2.1. Subjects Nine DMS patients (four males and five females) were diagnosed by two psychiatrists, on the basis of a sustained reduplicative delusion of misidentification. It should be noted that the DMS were defined and classified based on the consistency of the reduplicative delusion of misidentification and not on the transient character, as it occurs in mania and confused states. (Silva et al., 1990; Christodoulou, 1991). The patients were studied during their delusional episode. The sample of patients included four patients suffering from Capgras syndrome, two patients from Fre´goli syndrome, two from coexisting Capgras and Fre´goli syndrome and one patient suffering from Fre´goli syndrome and intermetamorphosis. All patients were psychotics of paranoid type according to DMS-IV criteria (American Psychiatric Association, 1994). Their mean age was 34.9 ± 7 years and their mean time spent in education was 12.9 ± 2.7 years. It should be noted that six patients in the DMS group were drug-free for at least 3 weeks before testing. It was not possible to keep all patients drug-free for ethical reasons. These three particular patients have taken medication as follows: the first patient trifluoperazine (30 mg/day) + carbamazepine (600 mg/day), the second patient risperidone (8 mg/day) + gabapentin (800 mg/day) and the third patient olanzapine (20 mg/day) + oxcarbazepine (600 mg/day). Patients were excluded if they had: (1) clinically significant neurological disease (including a seizure disorder); (2) a history of head injury; (3) speech or hearing difficulties; (4) a history of substance abuse or dependency on illicit drugs or alcohol. All patients underwent brain imaging investigation and their computerized tomography (CT) scans were normal. Eleven healthy volunteers (five males and six females) matched to the patients by age (34.2 ± 6.8 years) and educational level (13.2 ± 2.5 years), were recruited from hospital staff and local volunteer groups. All patients and control subjects were right-handed. Written informed consent was obtained from both patients and control subjects, and the study was approved by the local ethical committee. 2.2. Stimuli and procedure The auditory P300 of both groups was measured using a computerized version of the digit span test of Wechsler batteries (Wechsler, 1955; Conklin et al., 2000; Papageorgiou et al., 2002). The subjects sat in an anatomical chair placed inside an electromagnetically shielded room. An
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outline of the procedure is provided in Fig. 1. A single sound of either high (3000 Hz) or low frequency (500 Hz) was presented to the subjects, who were asked to memorize the numbers that followed. The warning stimulus lasted 100 ms. A 1-s interval followed and then the numbers to be memorized were presented. At the end of the number sequence presentation, the signal tone was repeated and subjects were asked to recall the administered numbers as quickly as possible. The numbers were recalled by the subject in the same (low frequency tone) or in the opposite order (high frequency tone) than that presented to him/her. Before any ERPs’ recording, a pre-process was performed so that the two sounds were differentiated by the subjects. According to this process, various trials have taken place until each subject understood both the different tonalities and the requirements of the test, concerning the storage and retrieval of presented numbers. After the completion of the abovementioned process, a rest period of five minutes followed, before the recording of the ERPs. ERPs were recorded during the 1-s interval between the warning stimulus and the first administered number. The electrophysiological signals were recorded through Ag/ AgCl electrodes. Electrode resistance was kept constantly below 5 kV. Electroencephalographic (EEG) activity was recorded from 15 scalp electrodes based on the International 10 –20 system of electroencephalography (Jasper, 1958), referred to both earlobes. An electrode placed on the subject’s forehead served as ground. The bandwidth of the amplifiers was set at 0.05 – 35 Hz. During the administration of stimuli, the subjects had their eyes closed in order to minimize eye movements and blinks. Eye movements were recorded through electrooculogram (EOG) and recordings with EOG higher than 75 mV were rejected. Warning stimuli, as well as learning material, i.e., the numbers to recall, were presented binaurally via earphones
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at an intensity of 65 dB sound pressure level. The evoked biopotential signal was submitted to an analog-to-digital conversion, at a sampling rate of 500 Hz, and was averaged by a computerized system. Each recording session consisted of 26 repetitions of the trial. Eye movements corresponding to EOG higher than 75 mV, resulting in rejection of the recording, ranged from 1 to 2 per investigation. Thus, the minimum number of artifact-free trials, that were averaged to produce an ERP, was 24. Since the warning stimuli were of two different frequencies, one high and one low, it was not clear whether they could generate the same P300, although the P300 component is included in the array of late-endogenous ERPs’ components, which normally are not modality specific (Fabiani et al., 2000). In order to ensure that there were no differences in the P300 waveforms caused by frequency modalities, we conducted t-test series comparisons between the P300 waveforms (amplitudes and latencies) evoked by the two frequency modalities (13 high and 13 low frequencies), in all subjects. No differences were found in the P300 waveforms, by frequency, in each subject. Consequently, the pooled P300 waveforms for each lead were used in the analysis. The following parameters were assessed: (a) ERPs were recorded for each subject at leads Fp1, Fp2, F3, F4, C3, C4, C3-T5/2, C4-T6/2, P3, P4, O1, O2, Pz, Cz and Fz. The positions C3-T5/2 and C4-T6/2 were used as electrode leads, because they correspond to brain areas for verbal memory and language (Binder, 1997). Recordings with acceptable EOGs were averaged, for each lead. The P300 was identified as the most positive peak in each averaged lead curve, between 240 and 500 ms after the warning stimulus. Peak amplitudes were measured relative to the mean amplitude of the 100-ms pre-stimulus baseline period and latency measurements were computed relative to stimulus onset. (b) The behavioral performance concerning recalled digits. 2.3. Statistical analysis
Fig. 1. Outline of experimental procedure.
Both groups of variables (amplitudes and latencies), as well as memory performance (numbers of recalled digits), were tested for statistical normality using the Kolmogorov – Smirnov goodness-of-fit test. Since all the P300 variables were found to be consistent with the normal distribution, one-way analysis of variance (ANOVA) tests were conducted to asses group differences. Results were considered significant at P < .05 level. Also forward conditional logistic regression models were applied in order to find the leads, which are most responsible for the discrimination of the two groups. The probability for entry was .05 and for removal was .1. Additionally, ANOVA was also conducted to assess group differences in memory performance measures, between DMS and control subjects. Results were considered significant at P < .05 level.
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3. Results 3.1. Comparison of P300 variables (amplitudes and latencies) Table 1 shows the mean values and standard deviations (S.D.) of the P300 amplitudes for the two groups, at each lead, while Fig. 2 demonstrates the mean values of the P300 amplitudes at each lead, in a pseudo-anatomical fashion. As the last column in Table 1 shows, statistically significant differences between the mean amplitude values of the two groups were found at leads F3, Fp2, F4, C4, Cz and Fz. The above leads were entered as independent variables into a stepwise logistic regression model with group as the dependent variable. Only lead F4 entered the regression equation, since the P300 amplitude values seem to be highly correlated between the leads. Nevertheless, the particular lead was able to classify correctly 90% of the subjects. Table 2 shows the mean values and S.D. of the P300 latencies for the two groups, at each lead. Fig. 3 demonstrates the mean values of the P300 amplitudes at each lead, in a pseudo-anatomical fashion. Statistically significant differences between the mean latency values of the two groups were found at leads Fp1, Fp2, F3, F4, C3, C4, C3-T5/2, P3, Pz, Cz and Fz (Table 2). The above leads were entered as independent variables into a stepwise logistic regression model with group as the dependent variable. Only lead Cz entered the regression equation, since the P300 latency values seem to be highly correlated between the leads. However, the particular lead was able to classify correctly 90% of the subjects. Averaged ERPs for both groups at the relevant leads (F4 and Cz) are presented in Fig. 4. Taking into consideration the possibility that the medication might had exerted a confounding influence on the
results, we conducted an additional statistical analysis excluding the three patients who were under medication. It is noteworthy that the results stand also after the exclusion of these patients. Particularly, with regard to the amplitude of P300, only lead F4 entered the regression equation, classifying correctly 100% of the subjects. As far as the latency of P300 is concerned, as in the case of the whole
Table 1 Mean amplitudes and S.D. (mV) of the P300 amplitude for the two groups, at each lead
Table2 Mean latencies and S.D. (ms) of the P300 latencies for the two groups, at each lead
DMS (n = 9)
Fp1 F3 C3-T5/2 C3 Fp2 F4 C4-T6/2 C4 O1 O2 P4 P3 Pz Cz Fz
Controls (n = 11)
Mean
S.D.
Mean
S.D.
9.2 9.6 8.4 12.1 5.9 7.2 6.1 8.8 9.5 10.5 9.6 11.7 10.7 11.8 8.7
10.2 7.3 6.6 7.5 5.7 4.8 5.7 4.1 5.1 5.7 5.1 9.2 6.1 5.5 6.6
16.48 16.70 12.2 15.8 16.2 16.7 11.0 14.0 8.5 7.2 10.2 11.9 15.0 17.7 19.5
6.2 4.6 3.4 5.3 5.5 4.6 4.8 4.3 4.2 3.8 4.6 3.9 4.8 5.9 5.6
The last column indicates statistical significance. * Indicates statistical significance at .05 level. ** Indicates statistical significance at .01 level.
Fig. 2. Mean values of the P300 amplitudes at each lead. White bars correspond to the DMS patients group and spotted bars correspond to the controls group. An asterisk denotes the lead, which is entered in the regression equation, classifying correctly 90% of the subjects.
DMS (n = 9)
P
.064 .017 * .115 .214 .001* * .001* * .058 .014 * .643 .142 .805 .946 .096 .037 * .001* *
Fp1 F3 C3-T5/2 C3 Fp2 F4 C4-T6/2 C4 O1 O2 P4 P3 Pz Cz Fz
Controls (n = 11)
Mean
S.D.
Mean
S.D.
370.0 354.4 335.5 367.8 354.0 354.7 348.0 357.3 390.4 362.9 373.8 372.0 373.3 364.0 352.4
82.5 86.0 78.4 80.4 86.8 87.7 75.3 89.4 75.5 81.6 73.4 76.5 79.9 82.3 87.6
274.4 250.7 278.4 268.9 261.3 256.0 289.8 282.9 320.4 356.5 312.2 269.8 268.5 246.2 250.0
29.6 17.0 33.7 33.3 25.7 24.4 76.6 59.6 96.0 81.6 84.5 34.6 34.9 14.6 16.8
The last column indicates statistical significance. * Indicates statistical significance at .05 level. * * Indicates statistical significance at .01 level.
P
.002* * .001* * .041 * .001* * .003* * .002* * .106 .039 * .091 .864 .103 .001* * .001* * .001 * .001* *
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4. Discussion
Fig. 3. Mean values of the P300 latencies at each lead. White bars correspond to the DMS patients group and spotted bars correspond to the controls group. An asterisk denotes the lead, which is entered in the regression equation, classifying correctly 90% of the subjects.
patients’ group, only lead Cz entered the regression equation, classifying correctly 90% of the subjects. 3.2. Comparison of memory performance (numbers of recalled digits) ANOVA revealed that patient group had significantly attenuated memory performance compared with healthy controls ( P < .001, F = 9.31, df = 32). The mean values and S.D. for the two groups, i.e., DMS and controls, were 54.4 ± 7.2 and 68.0 ± 4.5, respectively. More than 149 digits were presented.
The aim of the present study was to investigate the P300 elicited during a WM test in DMS patients, as compared to those of healthy controls. DMS patients showed significant reductions in P300 amplitude at the right frontal region compared to healthy controls. P300 latency in the central midline brain region was significantly prolonged in the DMS group. Each of these measures classifies correctly 90% of the two groups. Moreover, the memory performance of the patients group was significantly lower, relatively to healthy controls. It may be easier to understand the importance of the differences in P300 amplitude reported here, in the light of results from psychophysiological and neurobiological studies of this ERP component. These results indicate that P300 amplitude represents on-line updating of WM and/or attentional operations involved in WM (Donchin, 1981; Donchin and Coles, 1988; Holdstock and Rugg, 1995; Polich, 1998). It is suggested that frontal generators are more involved in automated orienting, while temporoparietal generators are more responsive to effortful processing of evoked stimuli. (Knight et al., 1989; Rogers et al., 1991; Ford et al., 1994; Higashima et al., 1996; Halgren et al., 1998; Winterer et al., 2001). However, recent studies in primates and humans indicate that frontal brain areas are also subjected to more complex experience-dependent dynamics (Fuster, 2000; Levy and Goldman-Rakic, 2000). Thus, on the basis of the obtained P300 amplitude results, it is reasonable to suggest, at least tentatively, that DMS patients may present defects in WM, being connected to the automatic nature of information processing mediated by the right frontal area, where it has been associated with complex experiencedependent dynamics. It has been also suggested that reduction in P300 amplitude may reflect gray matter abnormalities (McCarley et al., 1993; O’Donnell et al., 1993; Martin-Loeches et al., 2001). Therefore, an additional hypothesis, for the explanation of
Fig. 4. Grand average waveforms of DMS patients (gray line) and normal controls (black line) at leads F4 and Cz.
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the attenuation of the P300 amplitude found in the present work, might be the existence of gray matter degeneration. This hypothesis appears to be in accordance with recent brain imaging studies (Fleminger and Burns, 1993; PaillereMartinot et al., 1994; Mentis et al., 1995; Feinberg, 1997; Joseph et al., 1999), providing evidence of dysfunctional connections among frontal cortex, multimodal association areas and paralimbic structures, resulting in cognitive-perceptual-affective dissonance, which under specific conditions leads to positive delusional formation. Furthermore, the suggestion of dissonance agrees with a well documented hypothesis, that Capgras patients are able to recognize the misidentified person correctly but fail to receive any corresponding affective information (Ellis and Young, 1990; Ellis et al., 1997; Hirstein and Ramachandran, 1997). With regard to the P300 latency, our study revealed that the DMS group, compared to controls, showed a significant prolongation in the central midline brain region (lead Cz). It has been argued that prolonged P300 latency may reflect a failure to allocate attention resources to a stimulus (Coull 1998; Polich 1998) and/or ‘the transfer of information to consciousness’ (Picton, 1992). From a neurobiological perspective, prolonged latency may suggest the involvement of a neurodegenerative process (O’Donnell et al., 1995), affecting callosal size and the efficiency of inter-hemispheric transmission (Hoffman and Polich, 1999). Of course, it should be kept in mind that P300 does not allow estimation of callosal size or other structural changes in the brain. The differences reported here could imply that DMS patients may have difficulties in allocating attention resources to a stimulus, possibly due to a neurodegenerative process leading to impaired interhemispheric transmission. These findings seem to be broadly consistent with very recent results from Shah et al. (2001), who used functional magnetic resonance imaging (fMRI) to examine 10 healthy volunteers. The volunteers were exposed to familiar and unfamiliar faces and voices. Familiar stimuli were associated with increased activity in the posterior cingulate cortex, including the bilateral retrosplenial cortex. Thereby, this circuitry might account for the judgment of familiarity, which is a substantial issue of DMS. Our hypothesis is also compatible with observations in the classic disconnection syndrome called pure word blindness or alexia without agraphia, resulting from disruption of the corpus callosum, which interconnects the two hemispheres (Nolte, 1999). Patients with this rare condition can write (thus no agraphia) but are unable to read (alexia) even words they have just finished writing. Additionally, this assumption is supported by the study of Sergent (1990), who found that callosal defects may be involved in DMS processes. In the present study, there was a significant difference in memory performance between DMS patients and normal controls, indicating that DMS patients perform worse on digit span tests. This agrees with studies reporting that DMS patients show memory deficits (Morrison and Tarter, 1984;
Feinberg et al., 1999). These authors argued that being unable to associate new information with previous memories might lead to memory dysfunction in DMS. Our results should be interpreted with caution due to three limitations of the study. Firstly, sample sizes were inevitably small, since the DMS are very rare, and the main findings need to be replicated in independent samples. Secondly, post-hoc assignation of psychological function to regional activation is hypothetical, and more experiments with other neuroimaging (MRI) and/or metabolic techniques are warranted to address the role of specific psychological processes in relation to the functional anatomy and pathology of DMS patients. Finally, it is debatable whether the key features of DMS are specific to this condition or they are common to other psychiatric disorders, such as psychotic disorders. Thus, further studies comparing psychotic patients with DMS to the same category without DMS are needed.
5. Conclusions Present findings provide evidence supporting the hypothesis that DMS are associated with psychophysiological dysfunction linked with the right frontal region, which mediates automatic processes, as well as with an irregular allocation of attentional resources involving the interhemispheric circuitry, possibly due to gray matter degeneration. Given that P300 is seen as an endophenotype of the illness process, e.g., ‘a biological marker more proximal to the genes than the overt behavior’ (Ford et al., 2001), we suggest that further studies controlling trait-state parameters of these disorders will allow the investigation of correlations between genotype, endophenotype and phenotype. Studies that combine the time resolution of ERPs with the spatial resolution of brain imaging techniques could provide improved insight into the psychophysiological mechanisms, which underlie DMS, and may lead to clearer definitions of the brain function and structure of the syndromes. Acknowledgements The authors would like to thank the General Secretariat of Research and Technology of the Ministry of Development of Greece for funding this work. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Binder, J., 1997. Functional magnetic resonance imaging: language mapping. Neurosurg. Clin. N. Am. 8, 383 – 392. Boutros, N., Nasrallah, H., Leighty, R., Torello, M., Tueting, P., Olson, S., 1997. Auditory evoked potentials, clinical vs. research applications. Psychiatry Res. 69, 183 – 195.
C. Papageorgiou et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 365–372 Christodoulou, G.N., 1977. The syndrome of Capgras. Br. J. Psychiatry 1340, 556 – 564. Christodoulou, G.N., 1978. The syndrome of subjective doubles. Am. J. Psychiatry 135, 249 – 251. Christodoulou, G.N. (Ed.), 1986. The Delusional Misidentification Syndromes. Bibliotheca Psychiatrica, Basel. Christodoulou, G.N., 1991. The delusional misidentification syndromes. Br. J. Psychiatry 14, 65 – 69 (Suppl.). Conklin, H., Courtis, C., Katsanis, J., Iacono, W., 2000. Verbal working impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task. Am. J. Psychiatry 157, 275 – 277. Coull, J.T., 1998. Neural correlates of attention and arousal: insights from electrophysiology, functional neuroimaging and psychopharmacology. Prog. Neurobiol. 55, 343 – 361. Cutting, J., 1991. Delusional misidentification and the role of the right hemisphere in the appreciation of identity. Br. J. Psychiatry 14, 70 – 75 (Suppl.). Dejode, J.M., Antonini, F., Lagier, P., Martin, C., 2001. Capgras syndrome: a clinical manifestation of watershed cerebral infarct complicating the use of extracorporeal membrane oxygenation. Crit. Care 5, 232 – 235. Donchin, E., 1981. Surprise! . . . surprise? Psychophysiology 18, 493 – 513. Donchin, E., Coles, M.G.H., 1988. Is the P300 component a manifestation of cognitive updating? Behav. Brain Sci. 11, 357 – 427. Edelstyn, N.M., Oyebode, F., 1999. A review of the phenomenology and cognitive neuropsychological origins of the Capgras syndrome. Int. J. Geriatr. Psychiatry 4, 48 – 59. Ellis, H.D., Young, A.W., 1990. Accounting for delusional misidentifications. Br. J. Psychiatry 157, 239 – 248. Ellis, H.D., Young, A.W., Quayle, A.H., De Pauw, K.W., 1997. Reduced autonomic responses to faces in Capgras delusion. Proc. R. Soc. Lond., B Biol. Sci. 264, 1085 – 1092. Fabiani, M., Gratton, G., Coles, M., 2000. Event-related potentials: methods, theory, and applications. In: Cacioppo, J., Tassinary, L., Bernston, G. (Eds.), Handbook of Psychophysiology. Cambridge Univ. Press, New York, pp. 53 – 84. Feinberg, T.E., 1997. Some interesting perturbations of the self in neurology. Semin. Neurol. 17, 129 – 135. Feinberg, T.E., Eaton, L.A., Roane, D.M., Giacimo, J.T., 1999. Multiple Fre´goli delusions after traumatic brain injury. Cortex 35, 373 – 387. Fleminger, S., Burns, A., 1993. The delusional misidentification syndromes in patients with and without evidence of organic cerebral disorder: a structured review of case reports. Biol. Psychiatry 33, 22 – 32. Ford, J.M., Sullivan, E.V., Marsh, L., White, P.M., Lim, K.O., Pfefferbaum, A., 1994. The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged. Electroencephalogr. Clin. Neurophysiol. 90, 214 – 228. Ford, J.M., Mathalon, D.H., Kalba, S., Marsh, L., Pfefferbaum, A., 2001. N1 and P300 abnormalities in patients with schizophrenia, epilepsy, and epilepsy with schizophrenia-like features. Biol. Psychiatry 49, 848 – 860. Fuster, J.M., 2000. Executive frontal functions. Exp. Brain Res. 133, 66 – 70. Halgren, E., Marinkovic, K., Chauvel, P., 1998. Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr. Clin. Neurophysiol. 106, 156 – 164. Higashima, M., Kawasaki, Y., Urata, K., Maeda, Y., Sakai, N., Mizukoshi, C., Nagasawa, T., Kamiya, T., Yamaguchi, N., Koshino, Y., Matsuda, H., Tsuji, S., Sumiya, H., Hisasda, K., 1996. Simultaneous observation of regional cerebral blood flow and event-related potential during performance of an auditory task. Cogn. Brain Res. 4, 289 – 296. Hirono, N., Cummings, J.L., 1999. Neuropsychiatric aspects of dementia with Lewy bodies. Curr. Psychiatry Rep. 1, 85 – 92. Hirstein, W., Ramachandran, V.S., 1997. Capgras syndrome: a novel probe for understanding the neural representation of the identity and familiarity of persons. Proc. R. Soc. Lond., B Biol. Sci. 264, 437 – 444. Hoffman, L.D., Polich, J., 1999. P300, handedness, and corpus callosal size: gender, modality, and task. Int. J. Psychophysiol. 31, 163 – 174.
371
Holdstock, J.S., Rugg, M.D., 1995. The effect of attention on the P300 deflection elicited by novel sounds. J. Psychophysiol. 9, 18 – 31. Huang, T.L., Liu, C.Y., Yang, Y.Y., 1999. Capgras syndrome: analysis of nine cases. Psychiatry Clin. Neurosci. 53, 455 – 459. Jasper, H.H., 1958. The ten twenty electrode system of the international federation. Electroencephalogr. Clin. Neurophysiol. 10, 371 – 375. Joseph, A.B., 1986. Focal C.N.S. abnormalities in delusional misidentification syndromes. Bibl. Psychiatr. 164, 68 – 79. Joseph, A.B., 1994. Observations on the epidemiology of the delusional misidentification syndromes in the Boston metropolitan area: April 1983 – June 1984. Psychopathology 27, 150 – 153. Joseph, A.B., O’Leary, D.H., Kurland, R., Ellis, H.D., 1999. Bilateral anterior cortical atrophy and subcortical atrophy in reduplicative paramnesia: a case-control study of computed tomography in 10 patients. Can. J. Psychiatry 44, 685 – 689. Kirov, G., Jones, P., Lewis, S.W., 1994. Prevalence of delusional misidentification syndromes. Psychopathology 27, 148 – 149. Knight, R.T., Scabini, D., Woods, D.L., Claywort, C.C., 1989. Contribution of the temporo-parietal junction to the human auditory P3. Brain Res. 502, 109 – 116. Levy, R., Goldman-Rakic, P.S., 2000. Segregation of working memory functions within the dorsolateral prefrontal cortex. Exp. Brain Res. 133, 23 – 32. Luaute, J.P., Bidault, E., 1994. Capgras syndrome: agnosia of identification and delusion of reduplication. Psychopathology 27, 186 – 193. Martin-Loeches, M., Molina, V., Munoz, F., Hinojosa, J.A., Reig, S., Desco, M., Benito, C., Sanz, J., Gabiri, A., Sarramea, F., Santos, A., Palomo, T., 2001. P300 amplitude as a possible correlate of frontal degeneration in schizophrenia. Schizophr. Res. 49, 121 – 128. McAllister, T.W., 1992. Mixed neurologic and psychiatric disorders: pharmacological issues. Compr. Psychiatry 33, 296 – 304. McCarley, R., Shenton, M.E., O’Donnell, B.F., Faux, S.T., Kikinis, R., Nestor, P.G., Jolesz, F.A., 1993. Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch. Gen. Psychiatry 50, 190 – 197. Mentis, M.J., Weistein, E.A., Horwitz, B., McIntosh, A.R., Pietrini, P., Alexander, G.E., Furey, M., Murphy, D.G., 1995. Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. Biol. Psychiatry 38, 438 – 449. Morrison, R.L., Tarter, R.E., 1984. Neuropsychological findings relating to Capgras syndrome. Biol. Psychiatry 19, 1119 – 1128. Munro, A., 2000. Persistent delusional symptoms and disorders. In: Gelder, M.G., Lopez-Ibor, J.J., Andreasen, N. (Eds.), New Oxford Textbook of Psychiatry. Oxford Univ. Press, New York, pp. 651 – 676. Nolte, J., 1999. The Human Brain. An Introduction to its Functional Anatomy, 4th ed. Mosby, New York. O’Donnell, B.F., Shenton, M.E., McCarley, R.W., Faux, S.F., Smith, R.S., Salisbury, D.F., Nestor, P.G., Pollak, S.D., Kikinis, R., Jolesz, F.A., 1993. The auditory N2 component in schizophrenia: relationship to MRI temporal lobe gray matter and to other ERP abnormalities. Biol. Psychiatry 34, 26 – 40. O’Donnell, B.F., Faux, S.F., McCarley, R.W., Kimble, M.O., Salisbury, D.F., Nestor, P.G., Kikinis, R., Jolesz, F.A., Shenton, M.E., 1995. Increased rate of P300 latency prolongation with age in schizophrenia. Arch. Gen. Psychiatry 52, 544 – 549. Paillere-Martinot, M.L., Dao-Castellana, M.H., Masure, M.C., Pillon, B., Martinot, J.L., 1994. Delusional misidentification: a clinical, neuropsychological and brain imaging case study. Psychopathology 27, 200 – 210. Papageorgiou, C., Lykouras, L., Ventouras, E., Uzunoglu, N., Christodoulou, G.N., 2002. Abnormal P300 in a case of delusional misidentification with coinciding Capgras and Fre´goli symptoms. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 805 – 810. Phillips, M.L., David, A.L., 1995. Facial processing and delusional misidentification: cognitive neuropsychiatric approaches. Schizophr. Res. 17, 109 – 114.
372
C. Papageorgiou et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 365–372
Picton, T.W., 1992. The P300 wave of the human event-related potential. J. Clin. Neurophysiol. 9, 456 – 479. Polich, J., 1998. P300 clinical utility and control of variability. J. Clin. Neurophysiol. 15, 14 – 33. Roane, D.M., Rogers, J.D., Robinson, J.H., Feinberg, T.E., 1998. Delusional misidentification in association with parkinsonism. J. Neuropsychiatry Clin. Neurosci. 10, 194 – 198. Rogers, R.L., Bauman, S.B., Papanicolaou, A.C., Bourbon, T.W., Alagarsamy, S., Eisenberg, H.M., 1991. Localization of the P3 sources using magnetoencephalography and magnetic resonance imaging. Electroencephalogr. Clin. Neurophysiol. 79, 308 – 321. Sergent, J., 1990. Furtive incursions into bicameral minds. Brain 113, 537 – 568. Shah, N.J., Marshall, J.C., Zafiris, O., Schwab, A., Zilles, K., Markowitsch, H.J., Fink, G.R., 2001. The neural correlates of person familiarity. A functional magnetic resonance imaging study with clinical implications. Brain 124, 804 – 815. Silva, J.A., Leong, G.B., Shaner, A.L., 1990. A classification system for misidentification syndromes. Psychopathology 23, 27 – 32.
Silva, J.A., Leong, G.B., Weinstock, R., Klein, R.L., 1995. Psychiatric factors associated with dangerous misidentification delusions. Bull. Am. Acad. Psychiatry Law 23, 53 – 61. Silva, J.A., Leong, G.B., Rhodes, L.J., Weinstock, R., 1997a. A new variant of ‘‘subjective’’ delusional misidentification associated with aggression. J. Forensic Sci. 42, 406 – 410. Silva, J.A., Ferrari, M.M., Leong, G.B., Weinstock, R., 1997b. The role of mania in the genesis of dangerous delusional misidentification. J. Forensic Sci. 42, 670 – 674. Wechsler, D., 1955. Intelligence (WIS) WAIS Manual. Psychological Corporative, New York. Winterer, G., Mulert, C., Mientus, S., Gallinat, J., Schlattmann, P., Dorn, H., Herrmann, W.M., 2001. P300 and LORETA: comparison of normal subjects and schizophrenic patients. Brain Topogr. 13, 299 – 313. Zanker, S., 2000. Chronic and therapy refractory Fre´goli syndrome. Psychiatr. Prax. 27, 40 – 41.
Psychophysiological evidence for altered information processing in delusional misidentification syndromes Charalabos Papageorgioua,*, Errikos Ventourasb, Lefteris Lykourasa, Nikolaos Uzunogluc, George N. Christodouloua a
Psychophysiology Laboratory, Department of Psychiatry, Eginition Hospital, Medical School, University of Athens, 74 Vas. Sophias Avenue, Athens GR-11528, Greece b Department of Medical Instrumentation Technology, Technological Educational Institution of Athens, Egaleo, Athens, Greece c Department of Electrical and Computer Engineering, National Technical University of Athens, Zografou, Athens, Greece Accepted 18 November 2002
Abstract Recent research provides evidence that delusional misidentification syndromes (DMS) are associated with cognitive deficits. However, the underlying mechanisms of these deficits are not known. Since the P300 component of event-related potentials (ERPs) is related to fundamental aspects of working memory (WM), the present study is focused on P300 elicited during a WM test in DMS patients, as compared to those of healthy controls. Nine patients with DMS and 11 healthy controls, matched for age, sex and educational level were tested with a computerized version of the digit span test of the Wechsler batteries. Auditory ERPs were measured during the anticipatory period of the test. DMS patients showed significant reductions in P300 amplitude at the right frontal region compared to healthy controls. P300 latency in the central midline brain region was significantly prolonged in the DMS group. Each of these measures classified correctly 90% of the two groups. Moreover, the memory performance of the patient group was significantly lower, relatively to healthy controls. These findings provide evidence supporting the suggestion that DMS is associated with psychophysiological alterations occurring at the right frontal region, which mediates automatic processes, as well as with an irregular allocation of attentional resources, involving the interhemispheric circuitry, possibly due to gray matter degeneration. Finally, present work points to a need for further research investigating the characteristics, causes, course and treatment of severe cognitive deficits associated with DMS. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Capgras syndrome; Delusional misidentification syndromes; Event-related potentials; Fre´goli syndrome; P300; Working memory
1. Introduction The term delusional misidentification syndromes (DMS) includes the Capgras syndrome, the Fre´goli syndrome, intermetamorphosis and the syndrome of subjective doubles (Christodoulou, 1977, 1991). However, other types have been described, and it should be noted that individual cases may show features of more than one type (Christodoulou, 1978; Silva et al., 1997a). Interest in DMS has increased recently. Until the past decade, DMS was regarded as very
Abbreviations: CT, computerized tomography; DMS, delusional misidentification syndromes; EEG, electroencephalogram; EOG, electrooculogram; ERPs, event-related potentials; fMRI, functional magnetic resonance imaging; WM, working memory. * Corresponding author. Tel.: +30-107289117; fax: +30-107232042. E-mail address: [email protected] (C. Papageorgiou).
rare, but an increasing number of cases are now being reported (Joseph, 1994; Kirov et al., 1994; Huang et al., 1999). It has been suggested that DMS derive from ‘a failure to appreciate the actual identity or uniqueness of something—overriding the issue of whether it is a person, place, event or object’ (Cutting, 1991). A range of suggestions has been put forward, in order to explain the etiopathogenesis of DMS. Psychological and especially psychodynamic viewpoints attributed a decisive pathogenetic role to the defense mechanisms of splitting and projection, resulting from ambivalent feelings, induced by overintense affect towards significant others (Christodoulou, 1986; Zanker, 2000; Munro, 2000). It should be emphasized that, recently, the significance of these suggestions has been weakened, owing to the fact that a high proportion of DMS cases exhibit significant brain pathology, although the exact underlying mechanisms of this brain pathology is not clear.
0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. doi:10.1016/S0278-5846(02)00353-6
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However, it has been suggested that the disturbance in DMS is associated with defects in right hemispheric function and/ or interhemispheric transmission (Joseph, 1986; Fleminger and Burns, 1993; Hirono and Cummings, 1999; Luaute and Bidault, 1994; Mentis et al., 1995; Phillips and David, 1995; Edelstyn and Oyebode, 1999; Dejode et al., 2001). It is widely recognized that the elucidation of the fundamental nature of pathogenetic mechanisms of psychiatric entities may lead to new tools for treatment and prevention, individualization of care, harm reduction and cures. In this perspective event-related potentials (ERPs) constitute a useful tool, providing valuable information with regard to the brain-behavior relations (Boutros et al., 1997; Fabiani et al., 2000). One particular ERP component, the auditory P300 component, generated in response to a target detection task, that occurs about 300 ms after a warning stimuli, has received a great deal of interest. This ERP component is conceptualized as the physiological correlate of updating a cognitive hypothesis, or the working memory (WM) update of what is expected in the environment and/or attentional operations involved in this function (Donchin, 1981; Donchin and Coles, 1988; Polich, 1998; Coull, 1998). Until now, there has been a lack of empirical data concerning the ERP measures on DMS. Very recently (Papageorgiou et al., 2002), we observed a patient with concomitant Capgras and Fre´goli symptoms, who showed significant and diffuse prolongation of P300 latencies compared with healthy controls, as well as significantly attenuated amplitude of P300 in right prefrontal and parietal areas. Because the P300 component was elicited during a WM test, these findings may support the notion that DMS is associated with impairments of WM. In view of the above considerations, we hypothesize that the electrophysiological brain activity, as reflected by P300, in association with WM operations, could be of value in identifying possible pathophysiological mechanisms involved in DMS. Thus, the present study is focused on P300 elicited during a WM test in DMS patients, as compared to those of healthy controls, matched for age, sex and educational level. Furthermore, the decision was taken to investigate various DMS as a whole. It is interesting to note that DMS share a number of more or less common features, i.e., it is considered that these syndromes share a common neuroanatomical basis (see above). Additionally, it has been argued that these syndromes can arise as a dysfunction at one of several levels of familiarity processing during the information process (Phillips and David, 1995). Furthermore, on a clinical level of analysis, DMS demonstrate common features, i.e., they are selective and specific in that only one or a few ‘objects’ are misidentified. The fictitious ‘other’ is a personification or other symbolic representation of the patient’s own experience, and very often demonstrates aggression (Silva et al., 1995, 1997b). Finally, the dopamine overactivity (McAllister, 1992; Roane et al., 1998) is considered as an essential substrate of all DMS, while treatment involves antipsychotic medication in
all of them (Zanker, 2000). Consequently, the abovementioned points indicate that the various DMS might be linked by a potent association, thereby justifying their investigation as a whole.
2. Methods 2.1. Subjects Nine DMS patients (four males and five females) were diagnosed by two psychiatrists, on the basis of a sustained reduplicative delusion of misidentification. It should be noted that the DMS were defined and classified based on the consistency of the reduplicative delusion of misidentification and not on the transient character, as it occurs in mania and confused states. (Silva et al., 1990; Christodoulou, 1991). The patients were studied during their delusional episode. The sample of patients included four patients suffering from Capgras syndrome, two patients from Fre´goli syndrome, two from coexisting Capgras and Fre´goli syndrome and one patient suffering from Fre´goli syndrome and intermetamorphosis. All patients were psychotics of paranoid type according to DMS-IV criteria (American Psychiatric Association, 1994). Their mean age was 34.9 ± 7 years and their mean time spent in education was 12.9 ± 2.7 years. It should be noted that six patients in the DMS group were drug-free for at least 3 weeks before testing. It was not possible to keep all patients drug-free for ethical reasons. These three particular patients have taken medication as follows: the first patient trifluoperazine (30 mg/day) + carbamazepine (600 mg/day), the second patient risperidone (8 mg/day) + gabapentin (800 mg/day) and the third patient olanzapine (20 mg/day) + oxcarbazepine (600 mg/day). Patients were excluded if they had: (1) clinically significant neurological disease (including a seizure disorder); (2) a history of head injury; (3) speech or hearing difficulties; (4) a history of substance abuse or dependency on illicit drugs or alcohol. All patients underwent brain imaging investigation and their computerized tomography (CT) scans were normal. Eleven healthy volunteers (five males and six females) matched to the patients by age (34.2 ± 6.8 years) and educational level (13.2 ± 2.5 years), were recruited from hospital staff and local volunteer groups. All patients and control subjects were right-handed. Written informed consent was obtained from both patients and control subjects, and the study was approved by the local ethical committee. 2.2. Stimuli and procedure The auditory P300 of both groups was measured using a computerized version of the digit span test of Wechsler batteries (Wechsler, 1955; Conklin et al., 2000; Papageorgiou et al., 2002). The subjects sat in an anatomical chair placed inside an electromagnetically shielded room. An
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outline of the procedure is provided in Fig. 1. A single sound of either high (3000 Hz) or low frequency (500 Hz) was presented to the subjects, who were asked to memorize the numbers that followed. The warning stimulus lasted 100 ms. A 1-s interval followed and then the numbers to be memorized were presented. At the end of the number sequence presentation, the signal tone was repeated and subjects were asked to recall the administered numbers as quickly as possible. The numbers were recalled by the subject in the same (low frequency tone) or in the opposite order (high frequency tone) than that presented to him/her. Before any ERPs’ recording, a pre-process was performed so that the two sounds were differentiated by the subjects. According to this process, various trials have taken place until each subject understood both the different tonalities and the requirements of the test, concerning the storage and retrieval of presented numbers. After the completion of the abovementioned process, a rest period of five minutes followed, before the recording of the ERPs. ERPs were recorded during the 1-s interval between the warning stimulus and the first administered number. The electrophysiological signals were recorded through Ag/ AgCl electrodes. Electrode resistance was kept constantly below 5 kV. Electroencephalographic (EEG) activity was recorded from 15 scalp electrodes based on the International 10 –20 system of electroencephalography (Jasper, 1958), referred to both earlobes. An electrode placed on the subject’s forehead served as ground. The bandwidth of the amplifiers was set at 0.05 – 35 Hz. During the administration of stimuli, the subjects had their eyes closed in order to minimize eye movements and blinks. Eye movements were recorded through electrooculogram (EOG) and recordings with EOG higher than 75 mV were rejected. Warning stimuli, as well as learning material, i.e., the numbers to recall, were presented binaurally via earphones
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at an intensity of 65 dB sound pressure level. The evoked biopotential signal was submitted to an analog-to-digital conversion, at a sampling rate of 500 Hz, and was averaged by a computerized system. Each recording session consisted of 26 repetitions of the trial. Eye movements corresponding to EOG higher than 75 mV, resulting in rejection of the recording, ranged from 1 to 2 per investigation. Thus, the minimum number of artifact-free trials, that were averaged to produce an ERP, was 24. Since the warning stimuli were of two different frequencies, one high and one low, it was not clear whether they could generate the same P300, although the P300 component is included in the array of late-endogenous ERPs’ components, which normally are not modality specific (Fabiani et al., 2000). In order to ensure that there were no differences in the P300 waveforms caused by frequency modalities, we conducted t-test series comparisons between the P300 waveforms (amplitudes and latencies) evoked by the two frequency modalities (13 high and 13 low frequencies), in all subjects. No differences were found in the P300 waveforms, by frequency, in each subject. Consequently, the pooled P300 waveforms for each lead were used in the analysis. The following parameters were assessed: (a) ERPs were recorded for each subject at leads Fp1, Fp2, F3, F4, C3, C4, C3-T5/2, C4-T6/2, P3, P4, O1, O2, Pz, Cz and Fz. The positions C3-T5/2 and C4-T6/2 were used as electrode leads, because they correspond to brain areas for verbal memory and language (Binder, 1997). Recordings with acceptable EOGs were averaged, for each lead. The P300 was identified as the most positive peak in each averaged lead curve, between 240 and 500 ms after the warning stimulus. Peak amplitudes were measured relative to the mean amplitude of the 100-ms pre-stimulus baseline period and latency measurements were computed relative to stimulus onset. (b) The behavioral performance concerning recalled digits. 2.3. Statistical analysis
Fig. 1. Outline of experimental procedure.
Both groups of variables (amplitudes and latencies), as well as memory performance (numbers of recalled digits), were tested for statistical normality using the Kolmogorov – Smirnov goodness-of-fit test. Since all the P300 variables were found to be consistent with the normal distribution, one-way analysis of variance (ANOVA) tests were conducted to asses group differences. Results were considered significant at P < .05 level. Also forward conditional logistic regression models were applied in order to find the leads, which are most responsible for the discrimination of the two groups. The probability for entry was .05 and for removal was .1. Additionally, ANOVA was also conducted to assess group differences in memory performance measures, between DMS and control subjects. Results were considered significant at P < .05 level.
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3. Results 3.1. Comparison of P300 variables (amplitudes and latencies) Table 1 shows the mean values and standard deviations (S.D.) of the P300 amplitudes for the two groups, at each lead, while Fig. 2 demonstrates the mean values of the P300 amplitudes at each lead, in a pseudo-anatomical fashion. As the last column in Table 1 shows, statistically significant differences between the mean amplitude values of the two groups were found at leads F3, Fp2, F4, C4, Cz and Fz. The above leads were entered as independent variables into a stepwise logistic regression model with group as the dependent variable. Only lead F4 entered the regression equation, since the P300 amplitude values seem to be highly correlated between the leads. Nevertheless, the particular lead was able to classify correctly 90% of the subjects. Table 2 shows the mean values and S.D. of the P300 latencies for the two groups, at each lead. Fig. 3 demonstrates the mean values of the P300 amplitudes at each lead, in a pseudo-anatomical fashion. Statistically significant differences between the mean latency values of the two groups were found at leads Fp1, Fp2, F3, F4, C3, C4, C3-T5/2, P3, Pz, Cz and Fz (Table 2). The above leads were entered as independent variables into a stepwise logistic regression model with group as the dependent variable. Only lead Cz entered the regression equation, since the P300 latency values seem to be highly correlated between the leads. However, the particular lead was able to classify correctly 90% of the subjects. Averaged ERPs for both groups at the relevant leads (F4 and Cz) are presented in Fig. 4. Taking into consideration the possibility that the medication might had exerted a confounding influence on the
results, we conducted an additional statistical analysis excluding the three patients who were under medication. It is noteworthy that the results stand also after the exclusion of these patients. Particularly, with regard to the amplitude of P300, only lead F4 entered the regression equation, classifying correctly 100% of the subjects. As far as the latency of P300 is concerned, as in the case of the whole
Table 1 Mean amplitudes and S.D. (mV) of the P300 amplitude for the two groups, at each lead
Table2 Mean latencies and S.D. (ms) of the P300 latencies for the two groups, at each lead
DMS (n = 9)
Fp1 F3 C3-T5/2 C3 Fp2 F4 C4-T6/2 C4 O1 O2 P4 P3 Pz Cz Fz
Controls (n = 11)
Mean
S.D.
Mean
S.D.
9.2 9.6 8.4 12.1 5.9 7.2 6.1 8.8 9.5 10.5 9.6 11.7 10.7 11.8 8.7
10.2 7.3 6.6 7.5 5.7 4.8 5.7 4.1 5.1 5.7 5.1 9.2 6.1 5.5 6.6
16.48 16.70 12.2 15.8 16.2 16.7 11.0 14.0 8.5 7.2 10.2 11.9 15.0 17.7 19.5
6.2 4.6 3.4 5.3 5.5 4.6 4.8 4.3 4.2 3.8 4.6 3.9 4.8 5.9 5.6
The last column indicates statistical significance. * Indicates statistical significance at .05 level. ** Indicates statistical significance at .01 level.
Fig. 2. Mean values of the P300 amplitudes at each lead. White bars correspond to the DMS patients group and spotted bars correspond to the controls group. An asterisk denotes the lead, which is entered in the regression equation, classifying correctly 90% of the subjects.
DMS (n = 9)
P
.064 .017 * .115 .214 .001* * .001* * .058 .014 * .643 .142 .805 .946 .096 .037 * .001* *
Fp1 F3 C3-T5/2 C3 Fp2 F4 C4-T6/2 C4 O1 O2 P4 P3 Pz Cz Fz
Controls (n = 11)
Mean
S.D.
Mean
S.D.
370.0 354.4 335.5 367.8 354.0 354.7 348.0 357.3 390.4 362.9 373.8 372.0 373.3 364.0 352.4
82.5 86.0 78.4 80.4 86.8 87.7 75.3 89.4 75.5 81.6 73.4 76.5 79.9 82.3 87.6
274.4 250.7 278.4 268.9 261.3 256.0 289.8 282.9 320.4 356.5 312.2 269.8 268.5 246.2 250.0
29.6 17.0 33.7 33.3 25.7 24.4 76.6 59.6 96.0 81.6 84.5 34.6 34.9 14.6 16.8
The last column indicates statistical significance. * Indicates statistical significance at .05 level. * * Indicates statistical significance at .01 level.
P
.002* * .001* * .041 * .001* * .003* * .002* * .106 .039 * .091 .864 .103 .001* * .001* * .001 * .001* *
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4. Discussion
Fig. 3. Mean values of the P300 latencies at each lead. White bars correspond to the DMS patients group and spotted bars correspond to the controls group. An asterisk denotes the lead, which is entered in the regression equation, classifying correctly 90% of the subjects.
patients’ group, only lead Cz entered the regression equation, classifying correctly 90% of the subjects. 3.2. Comparison of memory performance (numbers of recalled digits) ANOVA revealed that patient group had significantly attenuated memory performance compared with healthy controls ( P < .001, F = 9.31, df = 32). The mean values and S.D. for the two groups, i.e., DMS and controls, were 54.4 ± 7.2 and 68.0 ± 4.5, respectively. More than 149 digits were presented.
The aim of the present study was to investigate the P300 elicited during a WM test in DMS patients, as compared to those of healthy controls. DMS patients showed significant reductions in P300 amplitude at the right frontal region compared to healthy controls. P300 latency in the central midline brain region was significantly prolonged in the DMS group. Each of these measures classifies correctly 90% of the two groups. Moreover, the memory performance of the patients group was significantly lower, relatively to healthy controls. It may be easier to understand the importance of the differences in P300 amplitude reported here, in the light of results from psychophysiological and neurobiological studies of this ERP component. These results indicate that P300 amplitude represents on-line updating of WM and/or attentional operations involved in WM (Donchin, 1981; Donchin and Coles, 1988; Holdstock and Rugg, 1995; Polich, 1998). It is suggested that frontal generators are more involved in automated orienting, while temporoparietal generators are more responsive to effortful processing of evoked stimuli. (Knight et al., 1989; Rogers et al., 1991; Ford et al., 1994; Higashima et al., 1996; Halgren et al., 1998; Winterer et al., 2001). However, recent studies in primates and humans indicate that frontal brain areas are also subjected to more complex experience-dependent dynamics (Fuster, 2000; Levy and Goldman-Rakic, 2000). Thus, on the basis of the obtained P300 amplitude results, it is reasonable to suggest, at least tentatively, that DMS patients may present defects in WM, being connected to the automatic nature of information processing mediated by the right frontal area, where it has been associated with complex experiencedependent dynamics. It has been also suggested that reduction in P300 amplitude may reflect gray matter abnormalities (McCarley et al., 1993; O’Donnell et al., 1993; Martin-Loeches et al., 2001). Therefore, an additional hypothesis, for the explanation of
Fig. 4. Grand average waveforms of DMS patients (gray line) and normal controls (black line) at leads F4 and Cz.
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the attenuation of the P300 amplitude found in the present work, might be the existence of gray matter degeneration. This hypothesis appears to be in accordance with recent brain imaging studies (Fleminger and Burns, 1993; PaillereMartinot et al., 1994; Mentis et al., 1995; Feinberg, 1997; Joseph et al., 1999), providing evidence of dysfunctional connections among frontal cortex, multimodal association areas and paralimbic structures, resulting in cognitive-perceptual-affective dissonance, which under specific conditions leads to positive delusional formation. Furthermore, the suggestion of dissonance agrees with a well documented hypothesis, that Capgras patients are able to recognize the misidentified person correctly but fail to receive any corresponding affective information (Ellis and Young, 1990; Ellis et al., 1997; Hirstein and Ramachandran, 1997). With regard to the P300 latency, our study revealed that the DMS group, compared to controls, showed a significant prolongation in the central midline brain region (lead Cz). It has been argued that prolonged P300 latency may reflect a failure to allocate attention resources to a stimulus (Coull 1998; Polich 1998) and/or ‘the transfer of information to consciousness’ (Picton, 1992). From a neurobiological perspective, prolonged latency may suggest the involvement of a neurodegenerative process (O’Donnell et al., 1995), affecting callosal size and the efficiency of inter-hemispheric transmission (Hoffman and Polich, 1999). Of course, it should be kept in mind that P300 does not allow estimation of callosal size or other structural changes in the brain. The differences reported here could imply that DMS patients may have difficulties in allocating attention resources to a stimulus, possibly due to a neurodegenerative process leading to impaired interhemispheric transmission. These findings seem to be broadly consistent with very recent results from Shah et al. (2001), who used functional magnetic resonance imaging (fMRI) to examine 10 healthy volunteers. The volunteers were exposed to familiar and unfamiliar faces and voices. Familiar stimuli were associated with increased activity in the posterior cingulate cortex, including the bilateral retrosplenial cortex. Thereby, this circuitry might account for the judgment of familiarity, which is a substantial issue of DMS. Our hypothesis is also compatible with observations in the classic disconnection syndrome called pure word blindness or alexia without agraphia, resulting from disruption of the corpus callosum, which interconnects the two hemispheres (Nolte, 1999). Patients with this rare condition can write (thus no agraphia) but are unable to read (alexia) even words they have just finished writing. Additionally, this assumption is supported by the study of Sergent (1990), who found that callosal defects may be involved in DMS processes. In the present study, there was a significant difference in memory performance between DMS patients and normal controls, indicating that DMS patients perform worse on digit span tests. This agrees with studies reporting that DMS patients show memory deficits (Morrison and Tarter, 1984;
Feinberg et al., 1999). These authors argued that being unable to associate new information with previous memories might lead to memory dysfunction in DMS. Our results should be interpreted with caution due to three limitations of the study. Firstly, sample sizes were inevitably small, since the DMS are very rare, and the main findings need to be replicated in independent samples. Secondly, post-hoc assignation of psychological function to regional activation is hypothetical, and more experiments with other neuroimaging (MRI) and/or metabolic techniques are warranted to address the role of specific psychological processes in relation to the functional anatomy and pathology of DMS patients. Finally, it is debatable whether the key features of DMS are specific to this condition or they are common to other psychiatric disorders, such as psychotic disorders. Thus, further studies comparing psychotic patients with DMS to the same category without DMS are needed.
5. Conclusions Present findings provide evidence supporting the hypothesis that DMS are associated with psychophysiological dysfunction linked with the right frontal region, which mediates automatic processes, as well as with an irregular allocation of attentional resources involving the interhemispheric circuitry, possibly due to gray matter degeneration. Given that P300 is seen as an endophenotype of the illness process, e.g., ‘a biological marker more proximal to the genes than the overt behavior’ (Ford et al., 2001), we suggest that further studies controlling trait-state parameters of these disorders will allow the investigation of correlations between genotype, endophenotype and phenotype. Studies that combine the time resolution of ERPs with the spatial resolution of brain imaging techniques could provide improved insight into the psychophysiological mechanisms, which underlie DMS, and may lead to clearer definitions of the brain function and structure of the syndromes. Acknowledgements The authors would like to thank the General Secretariat of Research and Technology of the Ministry of Development of Greece for funding this work. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC. Binder, J., 1997. Functional magnetic resonance imaging: language mapping. Neurosurg. Clin. N. Am. 8, 383 – 392. Boutros, N., Nasrallah, H., Leighty, R., Torello, M., Tueting, P., Olson, S., 1997. Auditory evoked potentials, clinical vs. research applications. Psychiatry Res. 69, 183 – 195.
C. Papageorgiou et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 365–372 Christodoulou, G.N., 1977. The syndrome of Capgras. Br. J. Psychiatry 1340, 556 – 564. Christodoulou, G.N., 1978. The syndrome of subjective doubles. Am. J. Psychiatry 135, 249 – 251. Christodoulou, G.N. (Ed.), 1986. The Delusional Misidentification Syndromes. Bibliotheca Psychiatrica, Basel. Christodoulou, G.N., 1991. The delusional misidentification syndromes. Br. J. Psychiatry 14, 65 – 69 (Suppl.). Conklin, H., Courtis, C., Katsanis, J., Iacono, W., 2000. Verbal working impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task. Am. J. Psychiatry 157, 275 – 277. Coull, J.T., 1998. Neural correlates of attention and arousal: insights from electrophysiology, functional neuroimaging and psychopharmacology. Prog. Neurobiol. 55, 343 – 361. Cutting, J., 1991. Delusional misidentification and the role of the right hemisphere in the appreciation of identity. Br. J. Psychiatry 14, 70 – 75 (Suppl.). Dejode, J.M., Antonini, F., Lagier, P., Martin, C., 2001. Capgras syndrome: a clinical manifestation of watershed cerebral infarct complicating the use of extracorporeal membrane oxygenation. Crit. Care 5, 232 – 235. Donchin, E., 1981. Surprise! . . . surprise? Psychophysiology 18, 493 – 513. Donchin, E., Coles, M.G.H., 1988. Is the P300 component a manifestation of cognitive updating? Behav. Brain Sci. 11, 357 – 427. Edelstyn, N.M., Oyebode, F., 1999. A review of the phenomenology and cognitive neuropsychological origins of the Capgras syndrome. Int. J. Geriatr. Psychiatry 4, 48 – 59. Ellis, H.D., Young, A.W., 1990. Accounting for delusional misidentifications. Br. J. Psychiatry 157, 239 – 248. Ellis, H.D., Young, A.W., Quayle, A.H., De Pauw, K.W., 1997. Reduced autonomic responses to faces in Capgras delusion. Proc. R. Soc. Lond., B Biol. Sci. 264, 1085 – 1092. Fabiani, M., Gratton, G., Coles, M., 2000. Event-related potentials: methods, theory, and applications. In: Cacioppo, J., Tassinary, L., Bernston, G. (Eds.), Handbook of Psychophysiology. Cambridge Univ. Press, New York, pp. 53 – 84. Feinberg, T.E., 1997. Some interesting perturbations of the self in neurology. Semin. Neurol. 17, 129 – 135. Feinberg, T.E., Eaton, L.A., Roane, D.M., Giacimo, J.T., 1999. Multiple Fre´goli delusions after traumatic brain injury. Cortex 35, 373 – 387. Fleminger, S., Burns, A., 1993. The delusional misidentification syndromes in patients with and without evidence of organic cerebral disorder: a structured review of case reports. Biol. Psychiatry 33, 22 – 32. Ford, J.M., Sullivan, E.V., Marsh, L., White, P.M., Lim, K.O., Pfefferbaum, A., 1994. The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged. Electroencephalogr. Clin. Neurophysiol. 90, 214 – 228. Ford, J.M., Mathalon, D.H., Kalba, S., Marsh, L., Pfefferbaum, A., 2001. N1 and P300 abnormalities in patients with schizophrenia, epilepsy, and epilepsy with schizophrenia-like features. Biol. Psychiatry 49, 848 – 860. Fuster, J.M., 2000. Executive frontal functions. Exp. Brain Res. 133, 66 – 70. Halgren, E., Marinkovic, K., Chauvel, P., 1998. Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr. Clin. Neurophysiol. 106, 156 – 164. Higashima, M., Kawasaki, Y., Urata, K., Maeda, Y., Sakai, N., Mizukoshi, C., Nagasawa, T., Kamiya, T., Yamaguchi, N., Koshino, Y., Matsuda, H., Tsuji, S., Sumiya, H., Hisasda, K., 1996. Simultaneous observation of regional cerebral blood flow and event-related potential during performance of an auditory task. Cogn. Brain Res. 4, 289 – 296. Hirono, N., Cummings, J.L., 1999. Neuropsychiatric aspects of dementia with Lewy bodies. Curr. Psychiatry Rep. 1, 85 – 92. Hirstein, W., Ramachandran, V.S., 1997. Capgras syndrome: a novel probe for understanding the neural representation of the identity and familiarity of persons. Proc. R. Soc. Lond., B Biol. Sci. 264, 437 – 444. Hoffman, L.D., Polich, J., 1999. P300, handedness, and corpus callosal size: gender, modality, and task. Int. J. Psychophysiol. 31, 163 – 174.
371
Holdstock, J.S., Rugg, M.D., 1995. The effect of attention on the P300 deflection elicited by novel sounds. J. Psychophysiol. 9, 18 – 31. Huang, T.L., Liu, C.Y., Yang, Y.Y., 1999. Capgras syndrome: analysis of nine cases. Psychiatry Clin. Neurosci. 53, 455 – 459. Jasper, H.H., 1958. The ten twenty electrode system of the international federation. Electroencephalogr. Clin. Neurophysiol. 10, 371 – 375. Joseph, A.B., 1986. Focal C.N.S. abnormalities in delusional misidentification syndromes. Bibl. Psychiatr. 164, 68 – 79. Joseph, A.B., 1994. Observations on the epidemiology of the delusional misidentification syndromes in the Boston metropolitan area: April 1983 – June 1984. Psychopathology 27, 150 – 153. Joseph, A.B., O’Leary, D.H., Kurland, R., Ellis, H.D., 1999. Bilateral anterior cortical atrophy and subcortical atrophy in reduplicative paramnesia: a case-control study of computed tomography in 10 patients. Can. J. Psychiatry 44, 685 – 689. Kirov, G., Jones, P., Lewis, S.W., 1994. Prevalence of delusional misidentification syndromes. Psychopathology 27, 148 – 149. Knight, R.T., Scabini, D., Woods, D.L., Claywort, C.C., 1989. Contribution of the temporo-parietal junction to the human auditory P3. Brain Res. 502, 109 – 116. Levy, R., Goldman-Rakic, P.S., 2000. Segregation of working memory functions within the dorsolateral prefrontal cortex. Exp. Brain Res. 133, 23 – 32. Luaute, J.P., Bidault, E., 1994. Capgras syndrome: agnosia of identification and delusion of reduplication. Psychopathology 27, 186 – 193. Martin-Loeches, M., Molina, V., Munoz, F., Hinojosa, J.A., Reig, S., Desco, M., Benito, C., Sanz, J., Gabiri, A., Sarramea, F., Santos, A., Palomo, T., 2001. P300 amplitude as a possible correlate of frontal degeneration in schizophrenia. Schizophr. Res. 49, 121 – 128. McAllister, T.W., 1992. Mixed neurologic and psychiatric disorders: pharmacological issues. Compr. Psychiatry 33, 296 – 304. McCarley, R., Shenton, M.E., O’Donnell, B.F., Faux, S.T., Kikinis, R., Nestor, P.G., Jolesz, F.A., 1993. Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch. Gen. Psychiatry 50, 190 – 197. Mentis, M.J., Weistein, E.A., Horwitz, B., McIntosh, A.R., Pietrini, P., Alexander, G.E., Furey, M., Murphy, D.G., 1995. Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. Biol. Psychiatry 38, 438 – 449. Morrison, R.L., Tarter, R.E., 1984. Neuropsychological findings relating to Capgras syndrome. Biol. Psychiatry 19, 1119 – 1128. Munro, A., 2000. Persistent delusional symptoms and disorders. In: Gelder, M.G., Lopez-Ibor, J.J., Andreasen, N. (Eds.), New Oxford Textbook of Psychiatry. Oxford Univ. Press, New York, pp. 651 – 676. Nolte, J., 1999. The Human Brain. An Introduction to its Functional Anatomy, 4th ed. Mosby, New York. O’Donnell, B.F., Shenton, M.E., McCarley, R.W., Faux, S.F., Smith, R.S., Salisbury, D.F., Nestor, P.G., Pollak, S.D., Kikinis, R., Jolesz, F.A., 1993. The auditory N2 component in schizophrenia: relationship to MRI temporal lobe gray matter and to other ERP abnormalities. Biol. Psychiatry 34, 26 – 40. O’Donnell, B.F., Faux, S.F., McCarley, R.W., Kimble, M.O., Salisbury, D.F., Nestor, P.G., Kikinis, R., Jolesz, F.A., Shenton, M.E., 1995. Increased rate of P300 latency prolongation with age in schizophrenia. Arch. Gen. Psychiatry 52, 544 – 549. Paillere-Martinot, M.L., Dao-Castellana, M.H., Masure, M.C., Pillon, B., Martinot, J.L., 1994. Delusional misidentification: a clinical, neuropsychological and brain imaging case study. Psychopathology 27, 200 – 210. Papageorgiou, C., Lykouras, L., Ventouras, E., Uzunoglu, N., Christodoulou, G.N., 2002. Abnormal P300 in a case of delusional misidentification with coinciding Capgras and Fre´goli symptoms. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 805 – 810. Phillips, M.L., David, A.L., 1995. Facial processing and delusional misidentification: cognitive neuropsychiatric approaches. Schizophr. Res. 17, 109 – 114.
372
C. Papageorgiou et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 365–372
Picton, T.W., 1992. The P300 wave of the human event-related potential. J. Clin. Neurophysiol. 9, 456 – 479. Polich, J., 1998. P300 clinical utility and control of variability. J. Clin. Neurophysiol. 15, 14 – 33. Roane, D.M., Rogers, J.D., Robinson, J.H., Feinberg, T.E., 1998. Delusional misidentification in association with parkinsonism. J. Neuropsychiatry Clin. Neurosci. 10, 194 – 198. Rogers, R.L., Bauman, S.B., Papanicolaou, A.C., Bourbon, T.W., Alagarsamy, S., Eisenberg, H.M., 1991. Localization of the P3 sources using magnetoencephalography and magnetic resonance imaging. Electroencephalogr. Clin. Neurophysiol. 79, 308 – 321. Sergent, J., 1990. Furtive incursions into bicameral minds. Brain 113, 537 – 568. Shah, N.J., Marshall, J.C., Zafiris, O., Schwab, A., Zilles, K., Markowitsch, H.J., Fink, G.R., 2001. The neural correlates of person familiarity. A functional magnetic resonance imaging study with clinical implications. Brain 124, 804 – 815. Silva, J.A., Leong, G.B., Shaner, A.L., 1990. A classification system for misidentification syndromes. Psychopathology 23, 27 – 32.
Silva, J.A., Leong, G.B., Weinstock, R., Klein, R.L., 1995. Psychiatric factors associated with dangerous misidentification delusions. Bull. Am. Acad. Psychiatry Law 23, 53 – 61. Silva, J.A., Leong, G.B., Rhodes, L.J., Weinstock, R., 1997a. A new variant of ‘‘subjective’’ delusional misidentification associated with aggression. J. Forensic Sci. 42, 406 – 410. Silva, J.A., Ferrari, M.M., Leong, G.B., Weinstock, R., 1997b. The role of mania in the genesis of dangerous delusional misidentification. J. Forensic Sci. 42, 670 – 674. Wechsler, D., 1955. Intelligence (WIS) WAIS Manual. Psychological Corporative, New York. Winterer, G., Mulert, C., Mientus, S., Gallinat, J., Schlattmann, P., Dorn, H., Herrmann, W.M., 2001. P300 and LORETA: comparison of normal subjects and schizophrenic patients. Brain Topogr. 13, 299 – 313. Zanker, S., 2000. Chronic and therapy refractory Fre´goli syndrome. Psychiatr. Prax. 27, 40 – 41.